Abstract
Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adolescent
-
Adult
-
Amino Acid Sequence
-
Binding Sites
-
Carrier Proteins / chemistry
-
Carrier Proteins / genetics*
-
Carrier Proteins / metabolism*
-
Child
-
Child, Preschool
-
Chromosome Mapping
-
Chromosomes, Human, Pair 1 / genetics*
-
Cloning, Molecular
-
Exons / genetics
-
Female
-
Fibroblasts
-
Genes, Recessive / genetics*
-
Homozygote
-
Humans
-
Hypercholesterolemia / genetics*
-
Hypercholesterolemia / metabolism
-
Hypercholesterolemia / physiopathology
-
Introns / genetics
-
Italy
-
Lebanon
-
Liver / metabolism
-
Male
-
Middle Aged
-
Molecular Sequence Data
-
Mutation / genetics*
-
Organ Specificity
-
Pedigree
-
Phosphotyrosine / metabolism
-
Protein Binding
-
RNA, Messenger / analysis
-
RNA, Messenger / genetics
-
Receptors, LDL / metabolism*
-
Sequence Alignment
-
Two-Hybrid System Techniques
Substances
-
Carrier Proteins
-
RNA, Messenger
-
Receptors, LDL
-
Phosphotyrosine